Pediatric auto-immune
encephalitis
Ajay Goenka, MD,* Mahesh Chikkannaiah, MD, and Gogi Kumar, MD
Pediatric Auto-Immune Encephalitis (PAE) is a neuro-inflamma-
tory disorder with a varied presentation. The discovery of the
Anti NMDA receptor and other antibodies as the causative
agents of PAE, has led to an increased need for guidelines for
diagnosis and management of these disorders. PAE remains a
challenging group of disorders due to their varying presenta-
tions and etiology with a prolonged clinical course. The wide
spectrum of clinical symptoms involves altered mental status,
movement disorders, acute behavioral changes, psychosis,
Introduction
AE is defined as a neuro-inflammatory disorder
P of the central nervous system that presents with
altered mental status, seizure, and/or focal neu-
rological deficits. PAE comprises a rapidly evolving
group of potentially treatable disorders that should be
considered in all pediatric encephalitis patients.1,2
They are clinically challenging due to their resem-
blance to infectious encephalitis and on occasion can
be triggered by infectious encephalitis (e.g., herpes
simplex encephalitis).3
While there have been multiple advances in pediat-
ric neuro-inflammatory disorders, encephalitis contin-
ues to account for significant mortality and morbidity
in children. Multiple etiologies have been defined for
pediatric encephalitis including viral, bacterial, and
autoimmune disorders but the majority of cases
(50%
70%) are idiopathic still lack a defined
etiology.4
6 The etiology of autoimmune encephalitis
has evolved over the last decade with the discovery of
multiple antibodies that target the neuronal cell sur-
face as well as intracellular antigens that cause
encephalitis. Education about specific antibody testing
to diagnose these disorders should facilitate early and
appropriate treatment.7-9
From the Dayton Children Hospital, Wright State University Boonshoft
School of Medicine, 1 Children Plaza, Dayton Ohio 45404.
*Corresponding author.
E-mail: goenkaa@childrensdayton.org
Curr Probl Pediatr Adolesc Health Care 2021;51:101031
1538-5442/$ - see front matter
Ó 2021 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.cppeds.2021.101031
Curr Probl Pediatr Adolesc Health Care, July 2021
delirium, seizures, and insomnia. This group of disorders was
recently recognized in the children.
This review provides clinicians with information on the most
common PAE disorders, the spectrum of their clinical presenta-
tion, diagnostic tests and treatment protocols based on the cur-
rent literature.
Curr Probl Pediatr Adolesc Health Care 2021; 51:101031
The California encephalitis project was a major
study for understanding pediatric encephalitis and
focused on its epidemiology. In that study, despite
extensive work-up for infectious etiology, in almost
63% of patient no clear etiology was established. The
frequency of anti-NMDA receptor encephalitis was
found to be higher than that of any viral encephali-
tis.10 Another recent study showed similar results with
anti-N-methyl-D-aspartate (anti-NMDA) receptor
encephalitis being the second most common cause of
PAE, acute disseminated encephalomyelitis was the
most common.11
In 2016 a clinical approach to the diagnosis of auto-
immune encephalitis was published by12 Graus et al,
for adults and children. The guidelines were based on
differential diagnosis and level of evidence for auto-
immune encephalitis (possible, probable, or definite).
The study focused on prompt immunotherapy because
auto antibody testing results might not be available
immediately and diagnosis and treatment might be
delayed. Although the study provides a guideline for
managing ill children, the wide spectrum of clinical
manifestations associated with PAE diagnosis remains
a major challenge.
Multiple studies have shown that early diagnosis of
encephalitis and treatment can lead to significant
improvement.13
15 PAE can be treated successfully
with immuno-modulatory agents if diagnosed early
during illness. Based on the antibody targets, PAE has
been divided into two groups, a) antibodies targeting
the neuronal cell surface b) antibodies targeting intra-
cellular antigens. Depending on the targeted antigens
there is a wide spectrum of presenting symptoms
1
including altered mental status, movement disorders,
acute behavioral changes, psychosis, delirium, seiz-
ures, and insomnia.13
15
This review paper will focus on PAE antibodies and
provide a practical clinical approach to diagnosis that
should be useful to clinicians.
Pathophysiology
The pathophysiology of autoimmune encephalitis in
children is complex and is not well understood. The
current understanding of the immunoglobulin G IgG
antibodies that affect the proteins on the nerve cells
came from the initial description of the antibodies
against the N-methyl-D-aspartate receptor (anti-
NMDAR).7 Significant progress has been made and
currently multiple antibodies have been described and
validated for the neuronal cell surface e.g., leucine
rich glioma inactivated protein 1, LGI 1; contactin-
associated protein-2 CASPR2.7
The pathogenic mechanisms vary based on the anti-
bodies for in Anti NMDAR encephalitis, the symp-
toms are due to hypo-function of the NMDA receptors
with no complement activation or neuronal degenera-
tion,7 whereas in Voltage Gated Potassium Channel
(VGKC) encephalitis the symptoms are predomi-
nantly secondary to activation of the complement
pathway leading to neuronal damage.16
18 These
mechanisms continue to explain the clinical symp-
toms (e.g., presence of altered mental status) in Anti
NMDAR encephalitis
Autoantibodies can be divided based on the location
of the target protein. Antibodies that bind to intracel-
lular antigens are general markers of autoimmunity.
The autoantibodies that bind to the extracellular anti-
gens are pathogenic and bind to either synaptic recep-
tors or ion channels.19,20 The number of identified
antibodies associated with various syndromes in chil-
dren have progressively increased in the last few
years. These antibodies can be classified based on the
symptoms, medical history and clinical findings.
Multiple triggering factors for PAE have been pro-
posed, the validated factors include tumor (e.g., ovar-
ian teratomas) and infection (herpes
encephalitis). 20
22
The autoantibodies bind to the neu-
ronal surface epitopes and cause either internalization
of target proteins leading to hypo-function or activa-
tion of complement causing a cascade of downstream
changes in the immune system leading to the clinical
manifestations.
2 Curr Probl Pediatr Adolesc Health Care, July 2021
When to suspect autoimmune
encephalitis in children
The diagnosis of PAE is difficult due to the varied
presentation and prolonged course. In addition, there
is overlap of the clinical symptoms among PAE and
other pediatric syndromes Table 2. PAE mimickers
include inflammatory brain diseases, infections, meta-
bolic diseases, and psychiatric disorders. Inability of
children to express their symptoms combined with
poor cooperation during the physical examination cre-
ate another challenge to identify the correct diagnosis.
Symptoms vary based on age sub-groups includ-
ing poor feeding and lethargy in infants, seizures,
choreoathetoid movements to acute psychosis in
adolescent children. Children are also at risk for
acute worsening of symptoms with permanent intel-
lectual impairment.
PAE symptoms can present during a post infectious
period e.g., Herpes encephalitis17,19,20
22 but typically
happen in normal children. The presenting symptoms
can include a prodromal symptom of fever, brief focal
seizure, fussiness and irritability in over 50% of
patients.23,24 The symptoms typically progress rapidly
within days to a few weeks but may progress gradu-
ally depending on the autoantibodies.
Movement disorders, seizure and alerted mental
status remain the most common clinical presenta-
tion of PAE. Seizures can be present during the
early or later stage of the disease, can manifest as
focal or generalized and are often multifocal.
Occasionally the seizures are medically intractable
with status epilepticus and require medical induced
coma.23,25 Movement disorders include ataxia,
chorea, dystonia, myoclonus, or tremor and can be
present in 30-60% of the patients depending on the
underlying antibodies. 25
29 Movement disorders
can also be highly refractory to standard treatments
with medications, including anti-epileptics
(AE).29,30
Alerted mental status and intellectual impairment is
present in varying types and severity are the hallmark
of encephalitis.31
33 The symptoms of alerted mental
status can include developmental regression, language
regression or speech impairment in younger children
to psychosis in adolescents. Mood and behavioral
problems include irritability, hyperactivity, insomnia
or hypersomnia and anger outbursts. Occasionally
these symptoms are associated with repetitive or ste-
reotypical behaviors that also contribute to diagnostic
difficulty.23,25 Psychiatric symptoms are predomi-
nantly present in adolescents and adults compared to
younger children. Symptoms can vary during the
course of the illness from mood swings and mild per-
sonality changes to fulminant psychosis.23,25 Acute
onset of psychiatric symptoms in a previously healthy
children are uncommon and warrant a workup for
underlying PAE before diagnosing a primary behav-
ioral health diagnosis. Due to the wide spectrum of
clinical presentation as well as evolution of symptoms
over the course of the disease, the child with encepha-
litis should be carefully monitored for cognitive
changes, seizures, movement abnormalities, or other
neurologic symptoms.34,35
Recent literature has shown that there is significant
difference in the clinical symptomatology between
children and adults with encephalitis. The difference
in symptoms may be explained by evolution of neuro-
nal circuits, neuro-receptor densities and myelination.
NMDAR-associated encephalitis in adults presents as
memory deficits, psychiatric manifestations, and cen-
tral hypoventilation compared to children who typi-
cally exhibit seizures and movement disorders.22,36
Also, Anti GAD associated syndrome in children is
not associated with the stiff-person syndrome or cere-
bellar degeneration seen in adults.22
Graus published12 the diagnostic criterion for diag-
nosis of possible PAE and provides a framework for
early diagnosis and treatment.
Panel 1 Diagnostic criteria for possible autoimmune
encephalitis.
Diagnosis can be made when all three of the follow-
ing criteria have been met:
1. Subacute onset (rapid progression of less than 3
months) of working memory deficits (short-term
memory loss), altered mental status*, or psychiatric
symptoms
2. At least one of the following:  New focal CNS
findings  Seizures not explained by a previously
known seizure disorder  CSF pleocytosis (white
blood cell count of more than five cells per mm
3. MRI features suggestive of encephalitisy
Reasonable exclusion of alternative causes.
*Altered mental status defined as decreased or
altered level of consciousness, lethargy, or personality
change. yBrain MRI hyperintense signal on T2-
weighted fluid-attenuated inversion recovery sequen-
ces highly restricted to one or both medial temporal
lobes (limbic encephalitis), or in multifocal areas
Curr Probl Pediatr Adolesc Health Care, July 2021
involving grey matter, white matter, or both compati-
ble with demyelination or inflammation
Work up
The work up is complex and is based on the specific
syndrome that is suspected based on the age and the
clinical presentation. Table 1) Initial investigations
to be considered for any child with suspected PAE
are listed in Table 2, these should be individualized
to each child.
The work up should include testing for inflammatory
markers such as ESR and CRP, complete blood count,
though they can be normal in pediatric patients.37,38
They should also undergo a drug screen for recreational
drug use and accidental ingestion of medications. Addi-
tional test includes known antibodies associated with
systemic autoimmune diseases (e.g., ANS, Anti TPO
antibodies). Due to the wide clinical spectrum, a wide
panel of antibody testing is preferred; serum studies
should be followed by CSF studies for pleocytosis,
decreased glucose or elevated protein levels. Specific
antibodies testing can be performed both on CSF and
blood.37 Additional tests include testing for infectious
encephalitis specific to the season and region where the
patient lives or has traveled.
CSF neopterin is a biomarker that can be elevated in
anti-NMDAR encephalitis and other encephalitides,
but normal in Pediatric Autoimmune Neuropsychiatric
Disorders Associated with Streptococcal Infections
(PANDAS).30 There is evidence that PAE (particularly
anti-NMDAR encephalitis) may be triggered by herpes
simplex virus encephalitis and Japanese encephalitis.31
MRI with and without gadolinium remains the imag-
ing study of choice. Although the MRI can be nega-
tive in about 50% of patients during the earlier stages
of the disease; evidence of inflammation of the brain
can be very helpful for diagnosis and staging as well
as follow up of the disease process.20,21,37,39,40 Com-
mon MRI lesions include high signal on T2 and fluid-
attenuated inversion recovery sequences, these lesions
can be localized or diffuse. The lesions may develop
over time, and cerebral atrophy may occur months
later.20,21,37 While the temporal lobe is often involved,
MRI abnormalities are not limited to the temporal
lobe. PAE may be present with a normal MRI
Brain.20,37,38
Other useful imaging modalities include functional
PET and SPECT studies to assess for brain dysfunc-
tion, but experience is limited in pediatric PAE.41,42
3
TABLE 1. Antibody Testing. Features and antibodies characteristic of autoimmune encephalitis in children and adolescents.
Syndrome Clinical Features
Anti-NMDA receptor Psychosis, Agitation,
encephalitis Seizures, Choreoathe-
toid movements,
Dyskinesia
Leucine-rich glioma- Confusion, working
inactivated1 memory deficit, mood
encephalitis changes, and often
seizures), hyponatre-
mia, and occasional
faciobrachial dystonic
seizures
Anti GABA Seizures, Hypertonicity,
Epilepsia partialis
continua
Antiglycine receptor Progressive encephalo-
encephalitis myelitis, rigidity and
myoclonus (PERM)
Anti-GAD encephalitis Limbic encephalitis
TABLE 2. Diagnostic workup for pediatric patients with suspected Autoimmune Encephalitis
Serum Inflammatory markers
Mitochondrial markers
Thyroid profile
Infective agents
Autoantibodies
Immune markers
Urine Porphyria
Infective markers
Overdose/Poisoning
Lumbar Puncture Inflammatory markers
Mitochondrial markers
Infective agents
Autoantibodies
Nasal Swab Infective agents
EEG Long term monitoring 24 h. (preferred)
MRI Brain With and without contrast preferred
EEG has a high sensitivity during the acute stages of
the disease, a long-term continuous EEG is preferred
over a spot routine EEG. EEG is not only helpful for
assessing focal or generalized seizures and epilepti-
form discharge but also shows evidence for neuronal
dysfunction such as diffuse or focal slowing. The
EEG changes can be non-specific but, may help to dis-
tinguish PAE from primary psychiatric disorders or
PANS. EEG patterns can vary based on age also, with
predominant generalized changes in children versus
more focal (temporal) in adults. Specific EEG patterns
have been described with some PAE e.g., “delta
4 Curr Probl Pediatr Adolesc Health Care, July 2021
Antibodies EEG MRI Etiology
Amino terminus of NR1 Delta Brush Nonspecific T2 hyperin- Ovarian teratoma, CNS
subunit of NMDA tensity. Can be normal infection (HSV),
receptor peripheral infection,
idiopathic
LGI1, Caspr2 Nonspecific Increased T2/ FLAIR Thymoma, idiopathic
signal in the mesial
temporal lobe
Alpha 1 beta 3 subunit Nonspecific Multifocal cortical/ sub- Idiopathic
of GABA-A receptor cortical lesions
Epitope common to Nonspecific Multifocal cortical/ sub- Rarely paraneoplastic,
alpha 1
3 subunits of cortical lesions idiopathic
glycine receptor
Glutamic acid decarbox- Nonspecific Nonspecific
ylase 65 or 67
Complete blood count and differential, Erythrocyte sedimentation rate, C-reactive
protein, ferritin
Lactate and Pyruvate
TSH, Free T4, anti
thyroid-stimulating hormone receptor antibodies
HSV 1/2, EBV, Infectious Mononucleosis, Lyme, ASO,
DsDNA, ANA, Anti Ro-la antibodies
IgA, IgM, Ig A levels
Acute porphyria
Leukocytes/Nitrite/Culture
Recreational Drug screen
CSF cell counts, protein, lactate, oligoclonal bands, Myelin Basic Protein
Lactate
HSV 1/2, EBV, Infectious Mononucleosis, Lyme, bacterial aerobic and anaerobic
culture
Auto-immune encephalitis panel
Respiratory viruses and mycoplasma PCR
Focal or generalized slowing, spikes, LPDs, (lateralizing periodic discharges), elec-
trographic seizures. Specific markers including delta brush for Anti-NMDAR
encephalitis
T1, T2, FLAIR, and diffusion-weighted sequences to assess for inflammation,
stroke, hemorrhage
brush” pattern and extreme spindles, in anti-NMDAR
encephalitis, but the sensitivity of these patterns for
diagnosis of anti-NMDAR encephalitis is low.18,43
Neurocognitive testing helps to assess language,
memory, processing speed and underlying anxiety and
can be helpful in differentiating PAE from conversion
disorders.44 A change in neurocognitive function from
the baseline may indicate PAE rather than a conver-
sion disorder.
Brain biopsy is not part of initial work up and is
rarely required due to improved availability of anti-
body panels and imaging studies. In rare cases a
TABLE 3. Common mimickers of Autoimmune Encephalitis in pediatric patients
Mimickers
Schizophrenia
Conversion Disorder
Medication ingestion/Overdose
PANDAS
Systemic lupus erythematosus
Rasmussen encephalitis
Hashimoto encephalopathy
Clinical Presentation
Delusions, hallucinations, disorga-
nized speech or behavior
Varied based on the person.
Include shaking, tremor, memory
loss
Varied based on the drugs. Include
agitation, psychosis, delirium,
seizures
Obsessive compulsive disorder,
tic disorder, mood and behavior
problems
acute confusion, lethargy, or
coma; chronic dementias;
depression, mania
Intractable seizures loss of motor
skills and speech, hemiparesis
Impairment of the cognition, atten-
tion, orientation, sleep-wake
cycle
Diagnosis
Clinical diagnosis based on diag-
nostic criteria.
History, normal EEG and investiga-
tions. Diagnosis of exclusion
Urine and serum drug test
Clinical diagnosis based on diag-
nostic criteria. Positive throat
culture for strep or history of
scarlet fever
EGG, MRI, and brain biopsy
Elevated antithyroid antibodies
Treatment
Psychotherapy and antipsychotic
agents
Psychology counseling
Varied
Prolonged Antibiotics, symptom-
atic for mood and behavior
IV steroid, immune- suppressants
Antiepileptic, IV steroids. IVIG for
acute management, immune-
suppressants for chronic therapy
Oral or IV steroids

focused stereo-guided brain biopsy can be performed
as part of initial work (e.g., Rasmussen encephalitis).
Once the clinician highly suspects a diagnosis of
PAE and autoantibody testing is positive, evaluation
for malignancy should be pursued if indicated. The
work up for underlying malignancy should be tailored
to the possible antibodies; immature ovarian terato-
mas accounts for 11.8% of all teratomas in NDMAR-
Ab encephalitis patients. The presence of a malignant
tumor is directly associated with a higher risk of death
but does not affect the neurological presentation. Para-
neoplastic etiology is rarely seen in children therefore
the onconeural antibodies (e.g., Hu or Ma2) are not
usually tested early in the workup.45
Acute treatment
Early diagnosis and initiation of treatment is crucial
to achieve a better outcome. Once there is a high sus-
picion for a diagnosis of PAE and positive autoanti-
body testing, immunotherapy should be started as
early as possible. The common mimickers (Table 3),
and infectious and oncologic entities should be con-
sidered prior to treatment for PAE.
The mainstay of treatment for PAE is immunother-
apy. The underlying etiology, malignancy or infec-
tion, should also be treated simultaneously.
First Line therapy: The treatment starts with the
high-dose corticosteroids (methylprednisolone 30 mg/
kg/day, up to 1 g daily, for 3
5 days), followed by or
combined with IVIg (2 g/kg divided over 2
5 days).
The corticosteroids provide the advantage of broad
mechanisms of action on the immune system and can
cross the blood
brain barrier. Although there are no
clear guidelines on tapering of the steroids, many
authors recommend tapering using 1
2 mg/kg/day
orally, on average for another 12 weeks, adjusting the
dose according to patient tolerance and side effects.
In more severe syndromes, other treatment options
include maintenance pulsed steroid or IVIG, ranging
from 6 to 12 months. Intravenous immunoglobulin
(IVIG) has broad immune modulatory properties. If
no benefit is noticed, plasma exchange (PLEX), 3
5
exchanges over 10 days, should be considered. Plasma
exchange (PLEX) can also be used as a first line ther-
apy in certain situations. Based on a recent study in
patients with Anti NMDA receptor encephalitis, the
author suggested that early PLEX, and concomitant
corticosteroid can be used in certain clinical scenarios.
In a recent study of children with Anti NMDA recep-
tor encephalitis, initial improvement in symptoms was
noticed after the 3rd round of PLEX.20
Second Line therapy: A significant proportion of
autoimmune encephalitis patients will respond to
first-line therapy and show improvement in the first
1
2 weeks after initiation of therapy. Second-line
therapy is usually reserved if there is no significant
clinical improvement after 10 days with the first-line
therapies. Most common second line therapies
include Rituximab and cyclophosphamide.

Curr Probl Pediatr Adolesc Health Care, July 2021 5

Rituximab (375 mg/m2 every week for 4 weeks) is
usually well tolerated in children and is preferred to
cyclophosphamide (750 mg/m2 monthly). Rituximab’s
primary mode of action is B-cell depletion but B-cell
depletion results in reduced pro-inflammatory CD4
and CD8 T-cell responses.46 Rituximab infusion
requires monitoring of the B-cell measurement at
2
4 weeks to assess for B-cell depletion. Periodic
monitoring of B cells and immunoglobulins is also
important to assess B-cell repopulation and
hypogammaglobulinemia.47,48
Cyclophosphamide can be used as a second line
alternative for Rituximab for patients with refractory
PAE. Cyclophosphamide provides a broad cellular
immune suppression response and is used intrave-
nously monthly over the course of 3
6 months. Based
on a recent study the author proposed that cyclophos-
phamide can be used in addition to Rituximab in chil-
dren with PAE. The study showed that 58 of 144
patients who received Rituximab required additional
cyclophosphamide with no significant side effects.
Based on the risk factors associated with cyclophos-
phamide including long-term risks of infertility and
secondary malignancy; cyclophosphamide recom-
mended dose is 750 mg/m2 monthly.49
Symptomatic treatment: Treatment of agitation and
seizure is a very important part of the therapy and is
often challenging. There is no evidence for one anti-
seizure medication being more effective than others
and the management depends on the type and duration
of seizures (focal vs generalized). Occasionally medi-
cation induced coma has to be used for status epilepti-
cus. Sedatives such as clonidine, benzodiazepines,
and ketamine have been used in the intensive care set-
ting for agitation and aggressive behavior.50 Anti-psy-
chotics especially neuroleptics are less effective than
non-convulsant with a higher risk of adverse events
(e.g. Neuroleptic malignant syndrome or rigidity) in
anti-NMDAR encephalitis.50
Workup for primary malignancy and specific onco-
logic treatment is essential. The importance was
emphasized in a published case of Anti NMDA recep-
tor encephalitis; the child’s symptoms improved after
surgical removal of the ovarian teratoma with no
immunosuppressants.51 Aggressive work for an under-
lying malignancy should include pelvic MRI and
whole-body PET scan.
6 Curr Probl Pediatr Adolesc Health Care, July 2021
Maintenance Therapy
No universal guideline has been proposed but
chronic immuno-suppressants (e.g., mycophenolate
mofetil, azathioprine) have been used only in patients
with PAE with a known risk for relapsing49 The regi-
men has to be tailored based on the child’s syndrome
and the risk factors for a relapsing course
Future treatment prospects
The use of Intrathecal steroids and methotrexate has
been reported in pediatric patients with anti-NMDAR
encephalitis resistant to both first- and second-line
immunosuppressant agents.52 Other promising future
therapies includes bortezomib, which is a protease
inhibitor and reduces plasma cells and antibody pro-
duction.53 Tocilizumab acts as an inhibitor of the pro-
inflammatory cytokine interleukin (IL)-6 and is cur-
rently being under researched for use in refractory
case of PAE.54
Anti-NMDA receptor encephalitis
Anti
N-methyl-D-aspartate receptor (anti-NMDAR)
is one of the most common recognizable PAE. Ini-
tially described by Dalmau et al.14,22 in 2007, it is
associated with CSF IgG antibodies against the
GluN1 subunit of the NMDA receptor. Infants and
children account for almost 37% of cases of all anti-
NMDAR encephalitis reported cases.18,39 The clinical
symptoms vary and almost half of the patients present
with fever, headache, and vomiting, followed by neu-
rological or emotional behavioral manifestations.19,20
With the increased awareness of anti-NMDAR
encephalitis and wide availability of appropriate anti-
body testing, the frequency of disease identification
has increased. Multiple studies have shown that earlier
treatment of the anti-NMDAR encephalitis in children
results in better outcome.
Clinical Symptoms
Clinical symptoms vary based on age, teenagers and
adults usually present with abnormal behavior with
irritability and insomnia, dyskinesias, memory deficits
and autonomic instability, whereas children generally
present with seizures and movement disorders.18,39
Abnormal behavior includes psychosis, delusions, hal-
lucinations, agitation, aggression, or catatonia.
Children with anti-NMDAR encephalitis, unlike
affected adults, are likely to experience prodromal
symptoms such fever, vomiting, or headache.11,55 In a
recent study on children with anti-NMDAR encephali-
tis adolescent patients presented with emotional
behavioral manifestations similar to adults, whereas
younger children generally presented with neurologi-
cal symptoms (77%) e.g. seizures. Autonomic dys-
function that is common in adults occurs less
frequently in children. Although more than 42% of
adults with anti-NMDAR encephalitis develop hypo-
ventilation, this occurred in only 16% in one series of
children.20
Diagnosis criterion (Graus et al) Diagnosis of auto-
immune encephalitis by standard testing is problem-
atic because there are few clinical or investigational
markers that distinguish anti-NMDAR positive cases
from those with negative titers.12
Probable: all three of the following criteria have
been met. Diagnosis can also be made in the presence
of three of the above groups of clinical symptoms
accompanied by a systemic teratoma
1. Rapid onset (less than 3 months) of at least four of
the six following major groups of symptoms:
Abnormal (psychiatric) behavior or cognitive dys-
function, Speech dysfunction (pressured speech,
verbal reduction, mutism), Seizures, Movement
disorder, dyskinesias, or rigidity/abnormal pos-
tures, Decreased level of consciousness Autonomic
dysfunction or central hypoventilation
2. At least one of the following laboratory study
results: Abnormal EEG (focal or diffuse slow or
disorganized activity, epileptic activity, or extreme
delta brush), CSF with pleocytosis or oligoclonal
bands
3. Reasonable exclusion of other disorders
Definite anti-NMDA receptor encephalitis
Diagnosis can be made in the presence of one or
more of the six major groups of symptoms and IgG
anti-GluN1 antibodies, after reasonable exclusion of
other disorders.
Curr Probl Pediatr Adolesc Health Care, July 2021
Specific EEG findings, “extreme delta brush” has
been identified in 30% of adult patients with anti-
NMDA receptor encephalitis. Overall, the electroen-
cephalogram (EEG) is abnormal in almost all patients.
It usually shows diffuse slowing of the background in
the delta-theta range, although some patients may
have focal slowing.56
The confirmative diagnosis is by detection of
NMDA receptor antibodies in serum or cerebrospinal
fluid. Normalized IgG levels in serum and cerebrospi-
nal fluid are compared and the levels can be indicative
of intrathecal synthesis of antibodies.57 Cerebrospinal
fluid antibody levels correlate better with illness out-
come than those of serum.58
Evaluation for underlying malignancy is an impor-
tant part of the diagnostic work-up. In children, the
presence of an underlying tumor, teratoma or other
neoplasm, is uncommon. The teratomas are more
common in adult population, approximately 56% of
women older than 18 years have unilateral or bilateral
teratomas of the ovary.39 In men, the presence of tera-
toma of the testis is rare, and this tumor has not been
reported in young boys with anti-NMDA receptor
encephalitis. MRI of the abdomen and pelvis is the
test of choice to identify teratomas of the ovary in
young girls.
Treatment
Although no standard of treatment has yet been
established, there is evidence that removal of the
tumor, when appropriate, and prompt immunotherapy
improve outcome. The first- and second-line therapy
recommendations are as described above.
If diagnosed and treated the prognosis is favorable,
based on a recent study almost 80% of patients have
substantial or full recovery.44 An ongoing study that
assessed the long-term outcome of 500 patients (chil-
dren and adults) found that some patients continue to
improve 2 years after symptom presentation.20
Mimickers of Auto-immune Encephalitis
The clinical spectrum of PAE in children has rapidly
expanded due to discovery of new antibodies. and new
etiologies for existing disorders have been proposed. It
is also very important to identify and assess for any
7
mimickers for PAE in children. Common mimickers polymerase chain reaction (PCR) and CSF and blood
of PAE in children includes central nervous system culture. The MRI and electroencephalography (EEG)
(CNS) infection, CNS malignancy, toxic/drug inges- may also be helpful but are often non-specific.
tion, non-convulsive status epilepticus, and emotional
behavioral conditions.
Acute onset of emotional behavioral symptoms in Conclusion
children should raise the suspicion for PAE. Common Pediatric autoimmune encephalitis is a group of dis-
symptoms include hallucinations, reduced speech, orders that presents with acute/subacute non-infec-
sleep disturbance, and cognitive difficulties. The pres- tious encephalitis and has a varied clinical
ence of autonomic instability, dyskinesia, rapid pro- presentation. The diagnosis is based on the clinical
gression of psychosis, CSF pleocytosis, and MRI/ features and specific biomarkers including neuroimag-
EEG abnormalities further indicate that the emotional/ ing and auto-antibodies. Early diagnosis and treatment
behavioral manifestations are are essential for better clinical
more likely to be due to autoim-
mune encephalitis.59 Autoimmune Encephalitis (AE) outcomes. Research in this field
is advancing rapidly, standard-
Large vessel CNS vasculitis is should be considered in children ized diagnostic and manage-
a rare pediatric disorder and presenting with acute onset of ment criteria should be
often presents as ischemic stroke prolonged or difficult to control formulated soon based on this
with symptoms including focal
motor weakness and speech def- seizures, a movement disorder research.
icits. The MRI findings includ- or emotional behavioral symp-
ing ischemic changes and toms, especially if preceded by Study funding
abnormalities such as aneurysm bacterial or viral infections. There was no funding for this
and beading are helpful to dis-
tinguish this from PAE. 60 manuscript.
Small-vessel CNS vasculitis is
often difficult to distinguish
Disclosure
from PAE due to overlapping Teenagers are more likely to The authors have no conflicts
symptoms of cognitive dysfunc- present with the acute onset of a of interest relevant to this arti-
tion, seizures, vision abnormali- behavioral health disorder com- cle to disclose.
ties. MRI findings of pared to younger children. Autoimmune Encephalitis
nonischemic lesions and brain (AE) should be considered in
biopsy showing inflammatory children presenting with acute
vessel wall changes are classical onset of prolonged or difficult
features of small-vessel CNS to control seizures, a movement
vasculitis and often helpful to
60
Strong clinical suspicion is disorder or emotional behav-
distinguish from PAE. needed to make an early diag- ioral symptoms, especially if
Infection-associated encepha- preceded by bacterial or viral
lopathy includes a wide array nosis and initiate treatment infections. Teenagers are more
of viral, bacterial and fungal before confirmation by detect- likely to present with the acute
etiology. The early symptoms ing antibodies in blood or CSF. onset of a behavioral health dis-
of fever altered mental status Early diagnosis and initiation of order compared to younger
and seizures can mimic PAE.
Diagnosis hinges crucially on
treatment is crucial to achieve a children. Strong clinical suspi-
cion is needed to make an early
lumbar puncture and cerebro- better clinical outcome. diagnosis and initiate treatment
spinal fluid (CSF) examination before confirmation by detect-
for specific antibodies, ing antibodies in blood or CSF.

8 Curr Probl Pediatr Adolesc Health Care, July 2021

Early diagnosis and initiation of treatment is crucial to 10. Gable MS, Sheriff H, Dalmau J, Tilley DH, Glaser CA. The
achieve a better clinical out-
come. Common mimickers of
AE in children include traumas, Common mimickers of AE
central nervous system (CNS) children include traumas, cen-
infection, CNS vasculitis, CNS tral nervous system (CNS) infec-
malignancies, toxic/drug inges- tion, CNS vasculitis, CNS
tion, nonconvulsive status epi-
lepticus, inborn errors of malignancies, toxic/drug
metabolism, and emotional tion, nonconvulsive status epi-
behavioral conditions. lepticus, inborn errors of
metabolism, and emotional
behavioral conditions.
Acknowledgment
This work was based on the
clinical experience at the Dayton children hospital
over last 10 years and extensive literature review.
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